Greg Sutherland, a neuropathologist at the University of Sydney in Australia, wrote a detailed evaluation of the paper that didn't make it into my article. Because it is so comprehensive, it's worth making available to readers. Because it is so long, it doesn't easily fit as an insert.So instead of placing this into my original story, I'm posting it as a separate blog post and linking back.

For those who want the short version, Sutherland thinks the drug is worth taking into clinical trials. He also praises the study design. However, he cautions that it's far from clear whether the experiments in mice provide a reliable guide to what would happen in human clinical trials.

Sutherland concludes:

"Overall this work advances our present knowledge of AD therapeutics rather than being a ‘revolutionary’ game changer. The study is well performed and addresses an important aspect of AD, namely, symptomatic treatment, at a time when most researchers are turning their attention to preclinical diagnosis and treatment. The latter goals remains elusive at present, but J147 looks ready-made for clinical trials."

And for those who wish to read Sutherland's entire critique, here it is:

Alzheimer’s disease (AD) is the most common form of dementia with estimates suggesting there will be about 115 million sufferers worldwide by 2050. This rapid increase is due to a combination of an ageing population and the failure of approved therapies such as donepezil to slow or prevent the neurodegenerative process. The symptoms of AD, that include , short term memory deficits result from the loss of neurons. As the disease advances neurons are lost over an increasing proportion of the brain resulting in a wider range of cognitive and eventually motor (movement) deficits.

There are two forms of AD; rare genetic forms that represent less than 5% of total cases and the common sporadic forms. The exact cause of the latter are unknown but the major risk factor is aging. Although AD is not inevitable, about one quarter of the population above 85 years of age will develop the disease. In contrast the rare genetic cases result from mutations in three genes.

These individuals succumb to the disease much earlier. The finding of mutations (first in 1991) allowed the development of transgenic mouse models. Here the human gene or often genes with the mutation(s) is incorporated into mouse embryos and expressed in some of the resulting animals.

These transgenic models are reasonable copies of the human disease but the transgene is permanently on at a single level and this might not equate to the physiological expression seen in humans. Furthermore the transgenic mice don’t experience the neuronal loss seen in the human brain of AD patients.

Overview of Work

Prior et al. based at the Salk Institute have conducted a very elegant study that incorporates many of the features of AD. They have used a double transgenic mouse model (two mutated human genes) but have deliberately waited until these mice are equivalent to old age in humans.

Their rationale is two fold. Firstly aging is the major risk factor for common forms of AD. Second most mouse models are treated at ages before their AD-type pathology fully develops. This is opposed to AD patients themselves whose pathology will be quite advanced when they are initially diagnosed and receive treatment. This latter may contribute to the poor translation of positive results from mice studies to human clinical trials.

Similarly Prior et al. have previously trialed their putative treatment, J147 in younger mice to good effect (see Chen et al. PLoS One 2011) but could it rescue the disease process at such an advanced stage.

Excitingly for Prior et al. this seems to be the case. Using a battery of behavioral tests and state-of-the-art monitoring they have shown that J147, a derivate of the curry ingredient and antioxidant, curcumin, can reverse symptoms of cognitive function in aged mice, including short-term memory.

They have also shown that the effects are equivalent or exceed donepezil (trade name = Aricept) along with a synergistic effect with the latter where symptoms in the transgenic mice are reduced even further. As the authors point out this is important because many of the patients that will be trialed on experimental drugs in the near future will already be on this treatment.

Summary

The major finding of this study is that J147 is efficacious at an advanced stage of the disease, a state where most patients will find themselves when they are initially diagnosed. Importantly J147 is rapidly taken up into the brain and appears to have wide safety margins. Prior et al. have also shown that it increases the expression of neuron survival factors that are known to be decreased in AD patients’ brains.

The Holy Grail for AD researchers is to find preclinical markers so that AD patients can be treated before the loss of neurons that results in their symptoms. However even if these were available it is likely that a drug such as J147 would be required in concert because areas of AD brain are affected progressively. (ie) varying areas of severity in the same patient.

However there are a few caveats that should be noted in considering the likely translation to success in human studies. Firstly the mouse models don’t experience the level of neuronal loss seen in patients so it is difficult to say if J147 is truly neuroprotective. Second, donepezil only provides transient improvement in AD so matching the performance of this drug is perhaps not so impressive. Having said this there is every reason to believe that J147 in combination with donepezil could improve present treatment options.

Overall this work advances our present knowledge of AD therapeutics rather than being a ‘revolutionary’ game changer. The study is well performed and addresses an important aspect of AD, namely, symptomatic treatment, at a time when most researchers are turning their attention to preclinical diagnosis and treatment. The latter goals remains elusive at present, but J147 looks ready-made for clinical trials.